The long term goals of this project are to enhance the clinical utility of single photon emission computer tomography (SPECT) to image in vivo Tc-99m-radiolabeled pharmaceutical distributions, and to improve SPECT quantification of important biodistribution parameters such as activities, concentrations, and volumes. Specifically, one clinical focus of this research involves the detection and characterization of regions of decreased myocardial perfusion following intravenous administration of Tc-99m-labeled sestamibi. A second clinical application relates to the investigation of improved approaches for radiation treatment planning. The focus of this tasks involves the use of quantitative SPECT lung perfusion imaging to assess the response of normal lung tissue to radiation treatment. The main hypothesis of this project is that it is possible to develop unified SPECT acquisition and reconstruction strategies for improved clinical imaging in all regions of the chest (that is, the lungs as well as the hear). We propose to investigate the hypothesis by i) developing and implementing appropriate asymmetric fan beam transmission data acquisition geometries to accurately determine maps of the linear attenuation coefficients; ii) developing and implementing combined fan beam/parallel beam, and fan beam/cone beam emission data acquisition geometries; iii) developing and implementing SPECT reconstruction strategies that accurately account for the effects of non-uniform attenuation, scatter and system geometric response for all regions of the thorax, and that have clinically acceptable reconstruction times. The use of the respiratory and/or electrocardiogram gated data acquisition, coupled with statistically based morphometric transformations will be investigated to reduce the degrading effects of motion blurring caused by respiratory and cardiac contractile motions, and to improve accuracy and reduce bias in the reconstructed image. This unified strategy offers the potential to improve the detection and characterization of areas of decreased myocardial perfusion. Also, the improved quantification of activities and concentrations in SPECT lung perfusion images will result in a new method to assess lung tissue response to radiation that may be used to develop improved approaches for radiation treatment of lung cancer. The newly developed SPECT acquisition and reconstruction methodology will be evaluated with Monte Carlo simulations, with experimentally acquired phantom data, and with pilot patient studies. Receiver operating characteristic studies will be used to evaluate the new SPECT imaging strategy for detection of myocardial perfusion defects.